Abstract
The activating transcription factor 5 (ATF5), also termed ATFx, is a member of the ATF/cAMP response element-binding protein (CREB) family of basic zipper proteins. ATF5 is an anti-apoptotic protein that is highly expressed in malignant glioma and is essential for glioma cell survival. Accumulating evidence indicates that human malignant gliomas are universally infected with human cytomegalovirus (HCMV). Recent studies have shown that HCMV may be resistant to the induction of apoptosis by disrupting cellular pathways in glioblastoma. To investigate the potential anti-apoptotic function of HCMV in glioma, malignant U87 glioma cells were infected with HCMV. The present study showed that HCMV infection suppressed apoptosis in glioblastoma U87 cells by regulating the expression of ATF5. Furthermore, in glioblastoma U87 cells, HCMV infection induced cellular proliferation in parallel with an increase in the expression level of ATF5 and B-cell lymphoma/leukemia-2 to Bcl-2-associated X protein ratio. Loss of ATF5 function was achieved using a dominant-negative form of ATF5 in U87 cells, whereby cells appeared to grow marginally following HCMV infection when compared with the control. However, the anti-apoptotic ability was appeared to decline in the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. These results indicate that ATF5 signaling pathways may be important in the anti-apoptotic activity of HCMV-infected glioblastoma cells; therefore, the anti-apoptotic molecular mechanisms of HCMV in human glioblastoma cells were investigated in the current study. Prevention of HCMV infection may present a potential and promising approach for the treatment of malignant gliomas.
Highlights
Glioblastomas are a devastating form of primary brain tumor
To determine the role of Activating transcription factor 5 (ATF5) expression in the human cytomegalovirus (HCMV)‐infected U87 glioblastoma cells, the proliferation ratio of U87 cells was examined in response to HCMV infection
ATF5 protein levels were upregulated (Fig. 1C and D; P
Summary
Glioblastomas are a devastating form of primary brain tumor. Due to the highly infiltrative and invasive nature of such tumors, it remains clinically intractable. Activating transcription factor 5 (ATF5) is a novel factor that is closely associated with tumor cell differentiation, proliferation and apoptosis. ATF5, an anti‐apoptotic factor, is highly expressed in malignant glioma and is important in the promotion of cell survival [5]. ATF5 loss of function induces apoptosis in a number of glioma and breast cancer cell lines [10,11], interfering with ATF5 function in non‐tumor brain cells has not been found to affect their survival [10]. The Bcl‐2 family of proteins includes anti‐apoptotic proteins, such as Bcl‐2, Bcl‐Xl and induced myeloid leukemia cell differentiation protein, and apoptotic proteins, such as Bcl-2 homologous antagonist/killer, Bcl‐2 associated X protein (BAX), BH3 interacting‐domain and B-cell lymphoma 2 interacting mediator of cell death. The regulation and balance of the Bcl‐2 family proteins in a particular cell results in the inhibition or induction of apoptotic signaling pathways [12,13,14]
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